HIV is a major public health burden in the United States, with over one million persons living with HIV and 56,000 new infections every year. In the era of combination anti-retroviral therapy (ART), HIV+ persons are living longer - approximately 30% of those living with HIV in the US are over 50. As this population ages, chronic medical conditions take on increasing individual and public health importance. Chronic obstructive pulmonary disease (COPD) is a common complication of aging in the HIV-uninfected population and is expected to contribute substantially to long-term outcomes in the HIV+ population. Of additional concern, HIV+ persons have higher prevalence of COPD compared to non-infected persons of the same age with similar smoking histories, suggesting that undetermined, unique features of HIV predispose to the development of COPD. The aging process in HIV+ persons is accelerated in several organ systems (including cardiac, neurologic, and immune) and is in part mediated by immune senescence and chronic inflammation, but the effects of premature aging in the lung in HIV have not been investigated. Because COPD in the non-HIV population is associated with aging, it is possible that accelerated aging also plays a role in HIV-associated COPD. The overall goal of this proposal is to evaluate the novel hypothesis that COPD in HIV is a manifestation of accelerated immune cell and lung cell aging. We will test this hypothesis through the following aims: 1) To test the hypothesis that systemic immune activation and immune senescence are increased in HIV+ individuals with COPD. 2) To test the hypothesis that pulmonary inflammation and pulmonary immune cell and epithelial cell senescence are increased in HIV+ persons with COPD. Using an established HIV+ cohort of 160 participants, we will analyze available banked blood and sputum for molecular signals of aging and inflammation, and then correlate these results with available pulmonary function testing and radiographic measures of COPD. In completing these studies, we will determine associations between inflammation, cellular aging, and lung function, thus taking the first step in investigating a novel pathway of HIV COPD. These investigations will be key to further mechanistic studies and to the development of directed therapies for HIV COPD. Training plan: This proposal will provide the candidate, a pulmonary fellow, with the opportunity to use and expand her COPD knowledge base while developing a background in HIV/AIDS and the immunology of aging. Through labwork, coursework, and conferences, the candidate will acquire training in basic science techniques, biostatistics, and clinical study design. The resources and experiences of her mentor Dr. Morris, an expert in HIV-related chronic lung diseases, combined with the collaborative research environment at the University of Pittsburgh, assure the candidate's successful development to an independent researcher. PUBLIC HEALTH RELEVANCE: Chronic obstructive pulmonary disease (COPD) is accelerated in HIV and may become more common as the HIV-infected population ages. The mechanisms by which COPD develops in HIV-infected persons are currently poorly understood. We will determine the role of accelerated aging and immune activation in HIV- associated COPD. The proposed research is relevant to public health because it proposes a new paradigm of obstructive lung disease in HIV and may suggest novel areas for treatment or prevention to impact the long- term health outcomes of this disease.